1. Field of the Invention
The present invention relates to the aerosolized delivery of hypertonic saline (HS) and other osmolytes to provide overnight nasal hydration to patients with all forms of chronic obstructive pulmonary disease (COPD) over a long period of time. The present invention also relates to a device and apparatus with a sufficient reservoir to accomplish the same.
2. Description of the Background
The mucosal surfaces at the interface between the environment and the body have evolved a number of “innate defenses”, i.e., protective mechanisms. A principal form of such innate defense is to cleanse these surfaces with liquid. Typically, the quantity of the liquid layer on a mucosal surface reflects the balance between epithelial liquid secretion, often reflecting active anion (Cl− and/or HCO3−) secretion coupled with water (and a cation counter-ion), and epithelial liquid absorption, often reflecting active Na+ absorption, coupled with water and counter anion (Cl− and/or HCO3−). Many diseases of mucosal surfaces are caused by too little protective liquid on those mucosal surfaces created by an imbalance between secretion (too little) and absorption (relatively too much). The defective salt transport processes that characterize these mucosal dysfunctions reside in the epithelial layer of the mucosal surface.
One approach to replenish the protective liquid layer on mucosal surfaces is to “re-balance” the system by blocking Na+ channel and liquid absorption. The epithelial protein that mediates the rate-limiting step of Na+ and liquid absorption is the epithelial Na+ channel (ENaC). ENaC is positioned on the apical surface of the epithelium, i.e. the mucosal surface-environmental interface. Therefore, to inhibit ENaC mediated Na+ and liquid absorption, an ENaC blocker of the amiloride class (which blocks from the extracellular domain of ENaC) must be delivered to the mucosal surface and, importantly, be maintained at this site, to achieve therapeutic utility. The present invention describes diseases characterized by too little liquid on mucosal surfaces and “topical” sodium channel blockers designed to exhibit the increased potency, reduced mucosal absorbtion, and slow dissociation (“unbinding” or detachment) from ENaC required for therapy of these diseases.
Chronic obstructive pulmonary diseases are characterized by dehydration of airway surfaces and the retention of mucous secretions in the lungs. Examples of such diseases include cystic fibrosis, chronic bronchitis, and primary or secondary ciliary dyskinesia. Such diseases affect approximately 15 million patients in the United States, and are the sixth leading cause of death. Other airway or pulmonary diseases characterized by the accumulation of retained mucous secretions include sinusitis (an inflammation of the paranasal sinuses associated with upper respiratory infection) and pneumonia.
U.S. Pat. No. 5,817,028 to Anderson describes a method for the provocation of air passage narrowing (for evaluating susceptibility to asthma) and/or the induction of sputum in subjects via the inhalation of mannitol. It is suggested that the same technique can be used to induce sputum and promote mucociliary clearance. Substances suggested include osmolytes such as sodium chloride, potassium chloride, mannitol and dextrose.
Chronic bronchitis (CB), including the most common lethal genetic form of chronic bronchitis, cystic fibrosis (CF), a disease that reflects the body's failure to clear mucus normally from the lungs, which ultimately produces chronic airways infection. In the normal lung, the primary defense against chronic intrapulmonary airways infection (chronic bronchitis) is mediated by the continuous clearance of mucus from bronchial airway surfaces. This function in health effectively removes from the lung potentially noxious toxins and pathogens. Recent data indicate that the initiating problem, i.e., the “basic defect,” in both CB and CF is the failure to clear mucus from airway surfaces. The failure to clear mucus reflects dehydration of airway surfaces that reflects an imbalance between the amount of liquid and mucin on airway surfaces. This “airway surface liquid” (ASL) is primarily composed of salt and water in proportions similar to plasma (i.e., isotonic). Mucin macromolecules organize into a well defined “mucus layer” which normally traps inhaled bacteria and is transported out of the lung via the actions of cilia which beat in a watery, low viscosity solution termed the “periciliary liquid” (PCL). In the disease state, there is an imbalance in the quantities of mucins (too much) and ASL (too little) on airway surfaces that produces airway surface dehydration. This dehydration leads to mucus concentration, reduction in the lubricant activity of the PCL, and a failure to clear mucus via ciliary activity to the mouth. The reduction in mechanical clearance of mucus from the lung leads to chronic airways inflammation and bacterial colonization of mucus adherent to airway surfaces. It is the chronic retention of bacteria, the failure of local antimicrobial substances to kill mucus-entrapped bacteria on a chronic basis, and the consequent chronic inflammatory responses of the body to this type of surface infection, that lead to the destruction of the lung in CB and CF.
The current afflicted population in the U.S. is 12,000,000 patients with the acquired (primarily from cigarette smoke exposure) form of chronic bronchitis and approximately 30,000 patients with the genetic form, cystic fibrosis. Approximately equal numbers of both populations are present in Europe. In Asia, there is little CF but the incidence of CB is high and, like the rest of the world, is increasing.
There is currently a large, unmet medical need for products that specifically treat CB and CF at the level of the basic defect that cause these diseases. The current therapies for chronic bronchitis and cystic fibrosis focus on treating the symptoms and/or the late effects of these diseases. Thus, for chronic bronchitis, β-agonists, inhaled steroids, anti-cholinergic agents, and oral theophyllines and phosphodiesterase inhibitors are all in development. However, none of these drugs treat effectively the fundamental problem of the failure to clear mucus from the lung. Similarly, in cystic fibrosis, the same spectrum of pharmacologic agents is used. These strategies have been complemented by more recent strategies designed to clear the CF lung of the DNA (“Pulmozyme”; Genentech) that has been deposited in the lung by neutrophils that have futilely attempted to kill the bacteria that grow in adherent mucus masses and through the use of inhaled antibiotics (“TOBI”) designed to augment the lungs' own killing mechanisms to rid the adherent mucus plaques of bacteria. A general principle of the body is that if the initiating lesion is not treated, in this case mucus retention/obstruction, bacterial infections became chronic and increasingly refractory to antimicrobial therapy. Thus, a major unmet therapeutic need for both CB and CF lung diseases is an effective means of re-hydrating airway mucus (i.e., restoring/expanding the volume of the ASL) and promoting its clearance, with bacteria, from the lung.
The inhalation of osmolytes/osmolyte solutions, such as hypertonic saline (3-12% preferred embodiment 7%) has been demonstrated to be a safe and effective treatment for individuals with cystic fibrosis. Inhaled hypertonic saline improves mucus hydration and clearance, and is associated with improvements in lung function, as well as, a reduction in the number of infectious exacerbations over one year (Donaldson et al. N. Engl. J. Med. 354, 3, Jan. 19, 2006, pp. 241-250) and Elkins et. al. (N. Engl. J. Med. 354, 3, Jan. 19, 2006, pp. 229-240).
A limitation of inhaled osmolytes to increase mucosal hydration is the durability of the therapeutic effect of the osmolytes. In cell based assays, the ability of the mucosal epithelium to efficiently absorb fluid results in the reversal of osmolyte-induced surface hydration. The relatively short therapeutic benefit of inhaled osmolytes can be overcome by increasing the number of treatments per day. For example, Donaldson et al. (N. Engl. J. Med. 354, 3, Jan. 19, 2006, pp. 241-250) showed inhaling 7% HS four times daily increased FEV1 by two fold greater than observed by Elkins et al. (N. Engl. J. Med. 354, 3, Jan. 19, 2006, pp. 229-240) in CF patients inhaling 7% HS twice daily. However, increasing the dosing frequency of hypertonic saline or other osmolytes is inconvenient for subjects in need thereof, requiring hours of time taking medications during the day.
Clearly, what are needed are treatments that are more effective at restoring the clearance of mucus from the lungs of patients with CB/CF. The value of these new therapies will be reflected in improvements in the quality and duration of life for both the CF and the CB populations.
In U.S. patent application Ser. No. 11/851,803, R. C. Boucher and M. R. Johnson describe a method to extend the duration of osmolyte therapy by co-administering a potent sodium channel blockers. The inhibition of epithelial sodium transport prevents the reabsorption of HS osmolytes, and thereby, slows mucosal fluid absorption and extends the duration of mucosal hydration. The present invention describes an alternative approach to improving both the therapeutic benefit and convenience to the of inhaled osmolyte treatments.